Devices and methods for controlling tremor

ABSTRACT

A peripheral nerve stimulator can be used to stimulate a peripheral nerve to treat essential tremor, Parkinson tremor, and other forms of tremor. The peripheral nerve stimulator can be either a noninvasive surface stimulator or an implanted stimulator. Stimulation can be electrical, mechanical, or chemical. Stimulation can be delivered using either an open loop system or a closed loop system with feedback.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/277,946, filed Sep. 27, 2016, titled “DEVICES AND METHODS FORCONTROLLING TREMOR,” which is in turn a continuation of U.S. patentapplication Ser. No. 14/805,385, filed Jul. 21, 2015, titled “DEVICESAND METHODS FOR CONTROLLING TREMOR,” now U.S. Pat. No. 9,452,287, whichis a continuation of International Patent Application No.PCT/US2014/012388, filed Jan. 21, 2014, titled “DEVICES AND METHODS FORCONTROLLING TREMOR,” now Publication No. WO 2014/113813, which claimspriority to U.S. Provisional Patent Application No. 61/754,945, filedJan. 21, 2013, titled “DEVICES AND METHODS FOR CONTROLLING TREMOR,” U.S.Provisional Patent Application No. 61/786,549, filed Mar. 15, 2013,titled “USER CONTROLLABLE DEVICE TO REDUCE ESSENTIAL TREMOR VIANEUROMODULATION,” U.S. Provisional Patent Application No. 61/815,919,filed Apr. 25, 2013, titled “DEVICES AND METHODS FOR INFLUENCINGPERIPHERAL NERVES TO TREAT ESSENTIAL TREMOR, PARKINSON'S DISEASE, ANDOTHER NEURODEGENERATIVE OR NEUROMUSCULAR DISORDERS,” U.S. ProvisionalPatent Application No. 61/822,215, filed May 10, 2013, titled “DEVICESAND METHODS FOR CONTROLLING TREMOR,” and U.S. Provisional PatentApplication No. 61/857,248, filed Jul. 23, 2013 and titled “DEVICES ANDMETHODS FOR CONTROLLING TREMOR,” each of the foregoing of which areherein incorporated by reference in their entireties.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

FIELD

Embodiments of the invention relate generally to systems, devices, andmethods for treating tremor, and more specifically relate to system,devices, and methods for treating tremor by stimulation of a peripheralnerve.

BACKGROUND

Essential tremor (ET) is the most common movement disorder, affecting anestimated 10 million patients in the U.S., with growing numbers due tothe aging population. The prevalence of ET rises with age, increasingfrom 6.3% of the population over 65, to above 20% in the population over95. ET is characterized by an involuntary oscillatory movement,typically between 4-12 Hz. It can produce oscillations in the voice andunwanted movements of the head and limbs. Tremor in the hands andforearm is especially prevalent and problematic because it makes itdifficult to write, type, eat, and drink. Unlike Parkinson's tremor,which exists at rest, essential tremor is postural and kinetic, meaningtremor is induced by holding a limb against gravity or during movement,respectively.

Disability with ET is variable, and ranges from embarrassment to theinability to live independently when tasks such as writing andself-feeding are not possible due to the uncontrolled movements of thehand and arm. Despite the high prevalence and high disability in manypatients with ET, there are insufficient treatment options to addresstremor.

The drugs used to treat tremor (e.g., Propanolol and Primidone) havebeen found to be effective in reducing tremor amplitude by only 50% inonly 60% of patients. These drugs have side effects that can be severeand are not tolerated by many patients with ET. An alternative treatmentis surgical implantation of a stimulator within the brain using deepbrain stimulation (DBS), which can be effective in reducing tremoramplitude by 90%, but is a highly invasive surgical procedure thatcarries significant risks and cannot be tolerated by many ET patients.Thus, there is a great need for alternative treatments for ET patientsthat reduce tremors without the side effects of drugs and without therisks of brain surgery.

Tremor is also a significant problem for patients with orthostatictremor, multiple sclerosis and Parkinson's Disease. A variety ofneurological disorders include tremor such as stroke, alcoholism,alcohol withdrawal, peripheral neuropathy, Wilson's disease,Creutzfeldt-Jacob disease, Guillain-Barre syndrome and fragile Xsyndrome, as well as brain tumors, low blood sugar, hyperthyroidism,hypoparathyroidism, insulinoma, normal aging, and traumatic braininjury. Stuttering or stammering may also be a form of tremor. Theunderlying etiology of tremor in these conditions may differ from ET;however, treatment options for some of these conditions are also limitedand alternative treatments are needed.

ET is thought to be caused by abnormalities in the circuit dynamicsassociated with movement production and control. Previous work has shownthat these circuit dynamics may be temporarily altered by cooling,topical analgesics and vibration. Previous work reported that electricalstimulation using transcutaneous electrical nerve stimulation (TENS) didnot improve tremor (Munhoz 2003). It was therefore surprising todiscover in our clinical study that circuit dynamics associated with ETcan be altered by peripheral nerve simulation resulting in a substantialreduction in the tremor of individuals with ET.

The present invention is a novel peripheral stimulation device to sendsignals along the sensory nerves to the central nervous system in orderto modify the abnormal network dynamics. Over time, this stimulationnormalizes the neural firing in the abnormal network and reduces tremor.While DBS stimulates the brain directly, our peripheral stimulationinfluences the abnormal brain circuit dynamics by sending signals alongthe sensory nerves that connect the periphery to the brain. Thisapproach is non-invasive and expected to avoid DBS's surgical risks andassociated problems with cognitive, declarative and spatial memorydysarthria, ataxia or gait disturbances. The peripheral nervestimulation may effectively treat tremors by dephasing, overriding orobscuring the abnormal brain circuit dynamics. Overriding, obscuring ortraining the brain to ignore the abnormal brain circuit dynamics followson hypotheses for the mechanisms of traditional DBS.

Perhaps the technology most closely related to our approach istranscutaneous electrical nerve stimulation (TENS). High-frequency TENS(50 to 250 Hz) is commonly used to treat pain, with the hypothesis thatexcitation of large, myelinated peripheral proprioceptive fibers(A-beta) blocks incoming pain signals. While the inconsistent clinicalresults achieved using TENS for pain control have led many to questionits use for treatment of pain, it is well documented that surfaceelectrical stimulation excites A-beta neurons. A-beta neuronscommunicate proprioceptive sensory information into the same braincircuits that are abnormal in diseases including ET and Parkinson'sdisease. Without being limited by any proposed mechanism of action, thishas led us to propose that neurostimulation could be used to exciteA-beta nerves and thereby improve tremor. This proposal is particularlysurprising because a previous study by Munhoz et al. failed to find anysignificant improvement in any of the tremor parameters tested afterapplication of TENS. See Munhoz et al., Acute Effect of TranscutaneousElectrical Nerve Stimulation on Tremor, Movement Disorders, 18(2),191-194 (2003).

SUMMARY OF THE DISCLOSURE

The present invention relates systems, devices, and methods for treatingtremor, and more specifically relate to system, devices, and methods fortreating tremor by stimulation of a peripheral nerve.

In some embodiments, a method of reducing tremor in a patient isprovided. The method includes placing a first peripheral nerve effectorat a first location relative to a first peripheral nerve; delivering afirst stimulus to the first peripheral nerve through the firstperipheral nerve effector; and reducing the tremor amplitude bymodifying the patient's neural network dynamics.

In some embodiments, the placing step comprises placing the firstperipheral nerve effector on the patient's skin and the first stimulusis an electrical stimulus applied to a skin surface.

In some embodiments, the first stimulus has an amplitude from about 0.1mA to 10 mA and a frequency from about 10 to 5000 Hz. In someembodiments, the first stimulus has an amplitude that is less than about15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 mA.

In some embodiments, the placing step comprises implanting the firstperipheral nerve effector in the patient and the first stimulus is anelectrical stimulus.

In some embodiments, the implanting step comprises injecting the firstperipheral nerve effector in the patient. In some embodiments, the firststimulus has an amplitude less than about 3 mA and a frequency fromabout 10 to 5000 Hz. In some embodiments, the first stimulus has anamplitude that is less than about 5, 4, 3, 2 or 1 mA.

In some embodiments, the peripheral nerve effector includes a powersource.

In some embodiments, the method further includes powering the firstperipheral nerve effector wirelessly through an externally located powersource.

In some embodiments, the first stimulus is vibrotactile.

In some embodiments, the first stimulus is chemical.

In some embodiments, the method further includes sensing motion of thepatient's extremity using a measurement unit to generate motion data;and determining tremor information from the motion data.

In some embodiments, the delivery step comprises delivering the firststimulus based on the tremor information.

In some embodiments, the tremor information comprises a maximumdeviation from a resting position for the patient's extremity.

In some embodiments, the tremor information comprises a resting positionfor the patient's extremity.

In some embodiments, the tremor information comprises tremor frequency,phase, and amplitude.

In some embodiments, the step of delivering the first stimulus comprisesdelivering a plurality of bursts of stimulation having a variabletemporal delay between the bursts of stimulation.

In some embodiments, the method further includes placing a secondperipheral nerve effector at a second location relative to a secondperipheral nerve; and delivering a second stimulus to the secondperipheral nerve through the second peripheral nerve effector.

In some embodiments, the method further includes determining a period ofthe patient's tremor, wherein the step of delivering the second stimuluscomprises offsetting delivery of the second stimulus from the deliveryof the first stimulus by a predetermined fraction or multiple of aperiod of the tremor.

In some embodiments, the method further includes dephasing thesynchronicity of a neural network in the patient's brain.

In some embodiments, the first location and second location are locatedon adjacent fingers.

In some embodiments, the first peripheral nerve and the secondperipheral nerve are adjacent nerves.

In some embodiments, the first peripheral nerve is the median nerve andthe second peripheral nerve is the ulnar or radial nerve.

In some embodiments, the first peripheral nerve and the secondperipheral nerve are somatotopically adjacent.

In some embodiments, the first stimulus has an amplitude that is below asensory threshold.

In some embodiments, the first stimulus is greater than 15 Hz.

In some embodiments, the first peripheral nerve carries proprioceptiveinformation from the patient's extremity.

In some embodiments, the method further includes determining a durationof efficacy of the first stimulus on reducing the tremor amplitude; anddelivering a second stimulus before the expiration of the duration ofefficacy.

In some embodiments, the step of determining the duration of effectcomprises analyzing multiple stimuli applications applied over apredetermined period of time.

In some embodiments, the step of determining the duration of efficacyfurther comprises determining an activity profile for the patient.

In some embodiments, the step of determining the duration of efficacyfurther comprises determining a profile of the tremor.

In some embodiments, the activity profile includes data regardingcaffeine and alcohol consumption.

In some embodiments, the method further includes placing a conductionpathway enhancer over the first peripheral nerve.

In some embodiments, the conduction pathway enhancer is a conductivetattoo.

In some embodiments, the conduction pathway enhancer comprises one ormore conductive strips.

In some embodiments, the first location is selected from the groupconsisting of a wrist, a forearm, a carpel tunnel, a finger, and anupper arm.

In some embodiments, a system for treating tremor in a patient isprovided. The device can include a decision unit; and an interface unitadapted to deliver electrical stimuli to a peripheral nerve, theinterface unit comprising a first peripheral nerve effector incommunication with the decision unit, the first peripheral nerveeffector comprising at least one electrode; wherein the decision unitcomprises a processor and a memory storing instructions that, whenexecuted by the processor, cause the decision unit to: deliver a firstelectrical stimulus to a first peripheral nerve through the firstperipheral nerve effector, the electrical stimulus configured by thecontroller to reduce tremor in the patient's extremity by modifying thepatient's neural network dynamics.

In some embodiments, the first electrical stimulus has an amplitude lessthan about 10 mA and a frequency from about 10 to 5000 Hz. In someembodiments, the amplitude is less than about 15, 14, 13, 12, 11, 10, 9,8, 7, 6, 5, 4, 3, 2, or 1 mA.

In some embodiments, the interface unit further comprises a secondperipheral nerve effector in communication with the decision unit, thesecond peripheral nerve effector comprising at least one electrode,wherein the memory storing instructions that, when executed by theprocessor, further cause the decision unit to deliver a secondelectrical stimulus to a second peripheral nerve in the patient'sextremity through the second peripheral nerve effector.

In some embodiments, the instructions, when executed by the processor,cause the decision unit to deliver the second electrical stimulus offsetin time from the first electrical stimulus by a predetermined fractionor multiple a period of the tremor.

In some embodiments, the first peripheral nerve effector is adapted tobe placed on a first finger and the second peripheral nerve effector isadapted to be placed on a second finger.

In some embodiments, the first peripheral nerve effector comprises aplurality of electrodes arranged in linear array. In some embodiments,the plurality of electrodes are spaced about 1 to 100 mm apart.

In some embodiments, the first peripheral nerve effector comprises aplurality of electrodes arranged in a two dimensional array.

In some embodiments, the memory storing instructions that, when executedby the processor, further cause the decision unit to select a subset ofthe plurality of electrodes based on a position of first peripheralnerve effector on the patient's extremity, wherein the selection of thesubset of the plurality of electrodes occurs each time the firstperipheral nerve effector is positioned or repositioned on theextremity.

In some embodiments, the plurality of electrodes are spaced about 1 to100 mm apart along a first axis and about 1 to 100 mm apart along asecond axis perpendicular to the first axis. In some embodiments, someof the electrodes are adjacent to each other to form a strip. In someembodiments, the spacing can be less than about 100, 90, 80, 70, 60, 50,40, 30, 20, 10, 5, 4, 3, 2, or 1 mm.

In some embodiments, the system further includes a measurement unit,wherein the memory storing instructions that, when executed by theprocessor, further cause the decision unit to: measure the movement ofthe patient's extremity using the measurement unit to generate motiondata; and determine a tremor frequency and magnitude based on ananalysis of the motion data.

In some embodiments, the analysis of the motion data comprises afrequency analysis of the spectral power of the movement data.

In some embodiments, the frequency analysis is restricted to betweenabout 4 to 12 Hz. In some embodiments, the frequency analysis isrestricted to approximately the expected frequency range of the tremoror tremors of concern.

In some embodiments, the analysis of the motion data is done on apredetermined length of time of the motion data.

In some embodiments, the decision unit is further adapted to determinetremor phase information based on the motion data and to deliver thefirst electrical stimulus based on the tremor phase information.

In some embodiments, the tremor phase information comprises peak tremordeviation, the decision unit being further adapted to deliver the firstelectrical stimulus at a time corresponding to the peak tremordeviation.

In some embodiments, the memory storing instructions that, when executedby the processor, further cause the decision unit to deliver the firstelectrical stimulus as a plurality of bursts of electrical stimulationhaving a variable temporal delay between the bursts of electricalstimulation.

In some embodiments, the memory storing instructions that, when executedby the processor, further cause the decision unit to set parameters ofthe first electrical stimulus based on the determined tremor frequency.

In some embodiments, the memory storing instructions that, when executedby the processor, further cause the decision unit to set parameters ofthe first electrical stimulus based on the determined tremor magnitude.

In some embodiments, the memory storing instructions that, when executedby the processor, further cause the decision unit to compare thedetermined tremor magnitude with a predetermined threshold; and whereinthe first electrical stimulus is delivered when the determined tremormagnitude exceeds a predetermined threshold.

In some embodiments, the electrode is adapted to deliver the firstelectrical stimulus through the patient's skin.

In some embodiments, the electrode is adapted to be implanted anddeliver the electrical In some embodiments, the decision unit comprisesa user interface adapted to accept input from a user to adjust aparameter of the first electrical stimulus.

In some embodiments, the memory further stores a library of one or morepredetermined stimulation protocols.

In some embodiments, the interface unit is integrated with the decisionunit.

In some embodiments, the interface unit and the decision unit areseparate from each other and have separate housings.

In some embodiments, the decision unit is configured to wirelesslyprovide power to, or communicate with, the interface unit.

In some embodiments, the system further includes a measurement unitlocated in the decision unit.

In some embodiments, the system further includes a measurement unitlocated in the interface unit.

In some embodiments, the decision unit is a computing device selectedfrom the group consisting of a smartphone, tablet and laptop.

In some embodiments, the system further includes a server incommunication with the computing device, the server configured toreceive from the computing device motion data along with a history ofthe electrical stimuli delivered to the patient.

In some embodiments, the server is programmed to: add the receivedmotion data and the history of the electrical stimuli delivered to thepatient to a database storing data from a plurality of patients.

In some embodiments, the server is programmed to: compare the receivedmotion data and the history of the electrical stimuli delivered to thepatient to the data stored in the database; determine a modifiedelectrical stimulus protocol based on the comparison of the receivedmotion data and the history of the electrical stimuli delivered to thepatient to the data stored in the database; and transmit the modifiedelectrical stimulus protocol to the computing device.

In some embodiments, the electronics are flexible and are disposed on aflexible substrate, which can be a sleeve, pad, band, or other housing.

In some embodiments, a system for monitoring tremor in a patient'sextremity is provided. The system can include an interface unit havingan inertial motion unit for capturing motion data, a power source and awireless transmitter and receiver, the interface unit adapted to be wornon the patient's extremity; and a processing unit in communication withthe interface unit, the processing unit configured to receive the motiondata from the interface unit, wherein the processing unit is programmedto: determine a tremor signature and profile over a predetermined periodof time based on an analysis of the motion data.

In some embodiments, the processing unit is a mobile phone.

In some embodiments, the system further includes a server incommunication with the mobile phone, the server configured to receivemotion data from the mobile phone.

In some embodiments, the processing unit is further programmed tocompare the tremor magnitude with a predetermined threshold.

In some embodiments, the processing unit is further programmed togenerate an alert when the tremor magnitude exceeds the predeterminedthreshold.

In some embodiments, the predetermined threshold is adjustable by thepatient.

In some embodiments, the processing unit is programmed to prompt thepatient to enter activity data, the activity data including adescription of the activity and a time the activity occurred.

In some embodiments, the processing unit is programmed to correlate theactivity data with the determined tremor frequency and magnitude.

In some embodiments, the activity data comprises consumption of caffeineor alcohol.

In some embodiments, the activity data comprises consumption of a drug.

We have invented a peripheral nerve stimulation device and method thateffectively reduces tremors without the side effects of drugs andwithout the risks of brain surgery. Our approach is safe, and in someembodiments non-invasive, and effective in reducing tremor. In someembodiments, the device may work by altering the neural circuit dynamicsassociated with essential tremor, Parkinson's tremor, and other tremors.The device is simple to use, comfortable, and adjustable to achieve thebest therapy for each patient.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe claims that follow. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 illustrates one embodiment of delivering stimulation to themedian nerve found to reduce tremor.

FIGS. 2A-2C illustrate treatment effect of an embodiment of peripheralnerve stimulation in a (FIG. 2A) mild, (FIG. 2B) moderate and (FIG. 2C)severe ET patient. It presents results of a clinical study in which apatient with essential tremor reduced tremor amplitude by theconfiguration of stimulation at 150 Hz frequency, 300 us, and for 40minutes of stimulation on-time. The tremor reduction, shown by comparingthe ET patient's ability to draw a spiral, was observed immediatelyafter the stimulation was turned off.

FIGS. 3A-3C illustrate wrist flexion-extension calculated fromgyroscopic data in subject B from FIGS. 2A-2C. FIG. 3A shows the tremorbefore treatment; FIG. 3B shows the reduction in tremor immediatelyafter treatment; FIG. 3C shows that the tremor reduction is maintainedtwenty minutes after the treatment.

FIG. 4 illustrates an example of ineffective treatment in a moderate ETpatient.

FIG. 5 illustrates various positions on a patient where the tremoraltering system can be located.

FIGS. 6A and 6B illustrate the major nerves innervating the hand andtheir distal branches.

FIGS. 7A-7D are block diagrams illustrating various embodiments of atremor altering system.

FIG. 8A illustrates an embodiment of an electrode pair used to excitenerves in different fingers, in which both electrodes are positioned onthe finger. FIG. 8B illustrates an alternative means of exciting nervesin different fingers, in which the second electrode is positioned at thewrist. FIG. 8C illustrates an embodiment of the placement of electrodeson the wrist to target different underlying nerves. FIGS. 8D and 8Eillustrate various stimulation sites.

FIG. 9A is a diagram showing an embodiment of an excitation scheme todephase the brain regions receiving sensory input from two fingers. FIG.9B is a diagram showing an embodiment of an excitation scheme to dephasethe brain regions receiving sensory input from four fingers.

FIGS. 10A-10C illustrate an embodiment where the position of the handmay determine the optimal stimulation duty cycle and timing.

FIG. 11 illustrates an embodiment of variable stimulation that changesfrequency over time.

FIG. 12 is a drawing showing an embodiment where the stimulator ischemical and two neuromodulating chemicals can be mixed to providetailored chemical stimulation.

FIGS. 13A and 13B illustrate various forms of user controls.

FIGS. 14A-14M illustrate various non-invasive or invasive embodiments ofthe tremor altering system. FIG. 14E is a drawing showing an embodimentin which the stimulator is mechanical. FIG. 14H illustrates anembodiment of a device having a form factor of a wrist watch. FIG. 14Iillustrates the back of the device shown in FIG. 14, showing theelectrodes which are the interface with the user. FIGS. 14J and 14Killustrate an embodiment of a disposable electrode interface that snapsinto place of the wrist watch form factor of the device housing. FIG.14L illustrates an embodiment of a self aligning snap feature thatallows the disposable electrode interface to snap into the housing ofthe device in a wrist watch form factor.

FIG. 14M is a drawing showing the potential placement of electrodesalong the spine in an embodiment of the device where the effector iselectrical.

FIGS. 15A-15C illustrate various embodiments of an array of electrodes.

FIG. 16A-16D illustrate various embodiments of conductive ink tattoos.

FIGS. 17A-17B is a diagram showing an embodiment of the positioning ofan accelerometer on the hand or wrist for measuring the patient'sactivity and tremor.

FIGS. 18A and 18B illustrate an example of spectral analysis ofgyroscopic motion data for a patient with a tremor centered at 6.5 Hz.

FIG. 19 illustrates the correlation of postural tremor with kinetictremor.

FIG. 20 illustrates an embodiment of a stimulation device that canrecord and transmit data, such as the tremor characteristics andstimulation history, to a data portal device, such as a smartphone, thattransmits the data to a cloud-based server.

FIGS. 21A-21D are flowcharts showing the monitoring, integration,analysis and display of data used to inform the users or improve thestimulation.

FIG. 22 is a flowchart showing the feedback logic.

FIG. 23 is a drawing showing an embodiment where the stimulator is anelectrode implanted at least partially subdermally.

FIGS. 24A-24D illustrate various embodiments of implantable devices andskin surface devices allowing wireless power and control.

FIGS. 25A-25F illustrate various geometries of electrodes for implantedelectrical stimulation.

FIGS. 26A-26B illustrate two preferred embodiments of the controlsmodule that is used to interact with the device. A control system forthe tremor device utilizes feedback to modify the stimulation. It is aclosed loop in which the stimulation is adjusted based on measurement ofthe activity and tremor.

DETAILED DESCRIPTION Definition of Terms

As used herein, the terms “stimulating” and “stimulator” generally referto delivery of a signal, stimulus, or impulse to neural tissue of thetargeted region. The effect of such stimulation on neuronal activity istermed “modulation;” however, for simplicity, the terms “stimulating”and “modulating,” and variants thereof, are sometimes usedinterchangeably herein. The effect of delivery of the signal to theneural tissue may be excitatory or inhibitory and may potentiate acuteand/or long-term changes in neuronal activity. For example, the effectof “stimulating” or “modulating” a neural tissue may comprise one ormore of the following effects: (a) depolarizing the neurons such thatthe neurons fire action potentials, (b) hyperpolarizing the neurons toinhibit action potentials, (c) depleting neurons ion stores to inhibitfiring action potentials (d) altering with proprioceptive input, (e)influencing muscle contractions, (f) affecting changes inneurotransmitter release or uptake, or (g) inhibiting firing.“Proprioception” refers to one's sensation of the relative position ofone's own body parts or the effort being employed to move one's bodypart. Proprioception may otherwise be referred to as somatosensory,kinesthetic or haptic sensation. A “proprioceptor” is a receptorproviding proprioceptive information to the nervous system and includesstretch receptors in muscles, joints, ligaments, and tendons as well asreceptors for pressure, temperature, light and sound. An “effector” isthe mechanism by which the device modulates the target nerve. Forexample, the “effector” may be electrical stimulation of the nerve ormechanical stimulation of proprioceptors.

“Electrical stimulation” refers to the application of electrical signalsto the soft-tissue and nerves of the targeted area. “Vibrotactilestimulation” refers to excitation of the proprioceptors, as byapplication of a biomechanical load to the soft-tissue and nerves of thetargeted area. Applying “thermal stimulation” refers to induced coolingor heating of the targeted area. Applying “chemical stimulation” refersto delivery of either chemical, drug or pharmaceutical agents capable ofstimulating neuronal activity in a nerve or in neural tissue exposed tosuch agent. This includes local anesthetic agents that affectneurotransmitter release or uptake in neurons, electrically excitablecells that process and transmit information through electrical andchemical signals. The “cloud” refers to a network of computerscommunication using real-time protocols such as the internet to analyze,display and interact with data across distributed devices.

Clinical Study

We evaluated the method of using peripheral nerve stimulation to alterthe circuit dynamics associated with ET in a clinical study. A device100 that delivers transcutaneous electrical nerve simulation (TENS)using surface electrodes 102 positioned on the palmar side of the wristwas used to stimulate the median nerve 104 with square waves at afrequency of 150 Hz with a pulse width of 300 microseconds for 40minutes, as illustrated in FIG. 1. Wires 106 were used in thisembodiment to connect the device 100 to the electrodes 102. It wassurprising to discover that the tremor was reduced because previous workreported that peripheral nerve stimulation using TENS did not improvetremor (Munhoz 2003, referenced above).

This electrical stimulation effectively reduced the tremor in subjectswith tremors ranging in severity from mild to severe. Kinetic tremorswere evaluated using a widely used measure of kinetic tremor: theArchimedes Spiral drawing task of the Fahn Tolosa Marin test. Posturaltremors were evaluated by measuring the angular velocity of gyroscopesworn on the back on the hand.

Three patients, represented as subject A, B and C in FIG. 2, showspirals drawn by subjects with mild, moderate and severe ET before andafter stimulation. The postural tremor reductions were 70%, 78% and 92%,respectively, in the subjects with mild, moderate and severe tremor.Postural tremor could also be reduced with electrical stimulation, andthis effect was maintained up to 45 minutes after the end of treatment.FIGS. 3A-3C shows the effect on wrist flexion-extension as determinedfrom gyroscopic data in subject B from FIG. 2 as a representativeexample. Fifteen minutes of treatment reduced the tremor amplitude from0.9 degrees (FIG. 3A) to 0.2 degrees (FIG. 3B). This reduction in tremoramplitude was maintained through 40 minutes of treatment. A measurementtaken 20 minutes after treatment showed the tremor amplitude continuedto be reduced and was maintained at 0.2 degrees (FIG. 3C). The tremorreduction was variable between subjects. Some subjects did not respondto therapy, as shown in FIG. 4.

Great therapeutic results were achieved by reducing the tremor insubjects with ET through the application of electrical stimulation. Thestimulation was able to reduce tremor during the treatment, immediatelyafter the treatment, and up to twenty minutes after treatment. To enablechronic use and allow patients with ET to integrate the treatment intotheir lives, it is important to make the system convenient to use andeffective over a long duration. The following innovations and devicesachieve this goal.

Device Location

The device stimulates the sensory nerves in order to modify the abnormalnetwork dynamics. Over time, this stimulation normalizes the neuralfiring in the abnormal network and reduces tremor. Preferentially, thestimulated nerve is a nerve that carries sensory proprioceptiveinformation from the limb affected by the tremor. The nerve may bemodulated directly, such as by electrical stimulation anywhere along oradjacent to a nerve carrying proprioceptive information. Alternatively,the target nerve may be modulated indirectly, such as by excitation ofthe proprioceptors that stimulate the target nerve. FIG. 5 shows accesspoints to nerves carrying proprioceptive information from a limb orvocal cords or larynx. These access points can include, but are notlimited to, the fingers (510), the hand (520), the wrist (530), thelower arm (540), the elbow (550), the upper arm (560), the shoulder(570), the spine (580) or the neck (590), foot, ankle, lower leg, knee,or upper leg. Nerves affecting proprioception can include, for example,the median, ulnar, radial, or other nerves in the hand, arm, and spinalarea, or along muscle or within joints. These regions target to thenerves may include the brachial plexus, medial nerves, radial nerves,and ulnar, dermal, or joint space nerves. These regions may also targetthe musculature including muscles of the shoulder, muscles of the arm,and muscles of the forearm, hand, or fingers. Muscles of the shouldermay include, by non-limiting example, the deltoid, teres major andsupraspinatus. Muscles of the arm may include the coracobrachialis andtriceps brachii. Muscles of the forearm may include the extensor carpiradialis longus, abductor pollicis longus, extensor carpi unlarnis, andflexor carpi ulnaris.

In a preferred location, the device interfaces with the dermal surfaceof the tremulous upper extremities of the user and appliesneuromodulatory signals to the nerve bundles selected from the groupconsisting of the brachial plexus, medial nerves, radial nerves, andulnar nerves or the excitable structures in the musculature of the upperextremities on the skin or within a joint.

Proprioceptors can be found for example in muscles, tendons, joints,skin, and the inner ear. Criteria defining candidate nerves for directmodulation include the location of the tremor to be reduced and theproximity of the nerve to the skin's surface, high density ofproprioceptive fibers, and distance from excitable pain receptors ormuscles. The median nerve targeted at the wrist and the ulnar nervetargeted at the elbow rank high by these criteria. Criteria definingcandidate location for indirect proprioceptive modulation include thedensity and type of proprioceptors. Pacinian corpuscles provideinformation about touch; Muscle spindles provide information aboutchanges in muscle length by triggering action potentials in the musclespindle afferent nerve when mechanically-gated ion channels open due tomuscle stretching; Golgi tendon organs provide information about muscletension. These structures may also be stimulated to alter circuitdynamics and reduce tremor.

The device targets the specific nerves that synapse on the abnormalbrain circuit. This synapse may be either direct, or through multiplerelay synapses. FIGS. 6A and 6B shows a set of representative nervesthat transmit proprioceptive information into the olivo-cerebellonetwork, a network that is abnormal in ET. These nerves include the(610) distal branches and main branches of the (620) median nerve and(630) ulnar nerve, as well as the (640) distal branches and mainbranches of the (650) radial nerve. In preferred embodiments, thisdevice targets the nerves inputting proprioceptive information from thehand, wrist and forearm.

In another embodiment, the combination of any parts described herewithin, may be used to affect the nerves associated with voice tremor,including but not limited to branches of the vagus nerve such as thesuperior laryngeal nerve or the recurrent laryngeal nerve.

Device Components: Various Embodiments

FIGS. 7A-7D are conceptual diagrams illustrating some embodiments of atremor altering system 700. System 700 includes a housing 720, one ormore effectors 730, one or more controls 740 in electrical communicationwith the effector 730, and one or more power sources 750. The housing720 can, in some embodiments, include an interface 760. The interfacefacilitates the coupling of the effector to the patient. For example,the interface can provide a physical, electrical, chemical, thermal ormagnetic connection between the device and the patient's nerve. Thehousing 720 can also, in some embodiments, include a sensor 780 todetect the tremor, memory 770, display 790, and processor 797. Thedevice in this embodiment may include a processor 797 coupled to theeffector which could perform computations and control of othercomponents. The device may also include a digital library stored on theprocessor 797 or memory 770 which could contain preloaded modulationprotocols. The device could include a controls module 740 thatcommunicates with the processor 797 and could be used by the user tocontrol stimulation parameters. The controls allow the user to adjustthe operation of the device. For example, the controls can be configuredto turn the device on, turn the device off, adjust a parameter of theeffector, such as the intensity. The device may include a sensor 780connected to the processor 797 which may detect information ofpredefined parameters and transmits said parameter information to theprocessor 797. The device may include a data storage unit 770 connectedto the sensor 780 and processor 797; and a power supply 750 may beconnected to the processor.

The device may further contain a display or indicators 790 tocommunicate with the user and report on the status of the device.Indicators are preferably a light-emitting diode (LED) or some visualindicator but can alternatively be an audio indicator. The informationmay include the battery power or the stimulation status.

The device might not have an Effector 730. It may be a diagnosticnon-therapeutic device. In a preferred embodiment, the Interface Unit704 would be worn on the tremoring limb to track the tremor over time.Providing feedback to the user of the device can make them aware oftheir tremor and allow monitoring over time. Even without therapeuticstimulation this biofeedback can help some individuals reduce theirtremor. Alternatively, the device might not have a Sensor 780. It may bea therapeutic non-diagnostic device.

In order to make the device small and simple, many of these componentscould be housed in a separate unit. Processing, controlling and possiblysensing may be done remotely in a Decision Unit 702, making theInterface Unit 704 that provides the therapeutic contact with thepatient compact, simple, and flexible for a variety of applications(FIGS. 7B-7D). This Decision Unit 702 may be a new device designed forthis application, or it may be integrated into an existing technologysuch as a smartphone. This would allow the system to be robust handheldform-factor with a reduced cost and size.

In a preferred embodiment shown in FIG. 7B, the Interface Unit 704 is animplant; the Effector 730 provides electrical stimulation of the nerves;the instruction set and power are transmitted wirelessly from anexternal device. Alternatively, the implanted Interface Unit 704 may bepowered with an on-board battery. Alternatively, the implanted InterfaceUnit 704 may contain a sensor 780 for direct detection of the tremor orneuromuscular activity detected by electroneurography (ENG) orelectromyography (EMG).

In the preferred embodiment shown in FIG. 7C, the Interface Unit 704 isworn on the surface of the body; the Effector 730 provides electricalstimulation of the underlying nerves or vibrotactile stimulation ofnearby proprioceptors. The sensor 780 could include motion sensorsincluding accelerometers, gyroscopes and magnetometers.

In the preferred embodiment shown in FIG. 7D, one or more sensor units780, sensing motion, temperature, etc. may be worn at differentlocations in the body. The effector 730 and decision unit 702 are aseparate entity worn at a different location on the body than thesensors 780. This is useful if stimulation of a nerve occurs in alocation where tremor is not as easily or accurately measured. Forinstance, a stimulation device 700 placed on the underside of the wristfor reducing hand tremor is highly effective. However, measuring tremorof the hand from the wrist using accelerometer or gyroscopes could provemore difficult; a sensor unit placed separately on the palm or backsideof the hand in a glove or worn as a ring on one of the digits would showgreater sensitivity towards hand tremor since it is located beyond wristjoint.

Effectors: General

The effector may function to modulate the neural tissue in the upperextremity region at which stimulation is directed. For example, theeffector can modify neuronal signals in the nerves and/or modify theflow or content of proprioceptive information. The effectors may bedelivered transcutaneously or subcutaneously. One or more effectors canbe used to influence the nerves. In some embodiments, the effector canbe excitatory to the nerve. In other embodiments, the effector can beinhibitory to the nerve. In some embodiments, the system can be used toexcite the nerve during some portions of the treatment and inhibit thenerve during other portions of the treatment.

Effector: Electrical Stimulation

In some embodiments, the effector may be an electrical stimulator.Electrical effectors can include an electrode, an electrode pair, anarray of electrodes or any device capable of delivering an electricalstimulation to a desired location. Electrical stimulation may betranscutaneous or subcutaneous. For example, transcutaneous electricalstimulation may be achieved with electrodes placed on the surface of theskin while subcutaneous electrical stimulation may be achieved with animplanted electrode positioned close to a nerve.

The stimulation parameters may be adjusted automatically, or controlledby the user. The stimulation parameters may include on/off, timeduration, intensity, pulse rate, pulse width, waveform shape, and theramp of pulse on and off. In one preferred embodiment the pulse rate maybe approximately 50 to 5000 Hz, and a preferred frequency of about 50 Hzto 300 Hz, or 150 Hz. A preferred pulse width may range from 50 to 500μs (micro-seconds), and a preferred pulse width may be approximately 300μs. The intensity of the electrical stimulation may vary from mA to 500mA, and a preferred current may be approximately 1 to 6 mA. Thesepreferred settings are derived from the clinical study described abovethat provided a valuable reduction in tremor sustained for a timeperiod. We note that the electrical stimulation can be adjusted indifferent patients and with different methods of electrical stimulation;thus, these preferred settings are non-limiting examples. The incrementof intensity adjustment may be 0.1 mA to 1.0 mA. In one preferredembodiment the stimulation may last for approximately 10 minutes to 1hour.

In one preferred embodiment, the electrodes may be in contact with theuser at the surface of the skin above one or more nerve(s) that mayinclude the medial, radial, and ulnar nerves. The electrode may be inthe configuration where there is an electrode pair, in which oneelectrode is proximal (closer to the elbow) and another is distal(closer to the hand). The electrodes may be in communication with theopposing electrode. The electrode pair may have a polarity of positiveor negative charge in which electrical current passes.

The effector may include two electrodes, each with positive or negativepolarity, or an electrode array may include multiple electrode pairs,where each pair is independently programmed or programmed dependently inrelation to the other pairs of electrodes. As an example, the programcan allow cyclic stimulation of different nerves at different times,such as ulnar, then median, then radial, or any combination thereof.

Electrical stimulation may be designed to suppress tremors byinterfering with proprioceptive input, inducing compensatory musclecontractions, or by a combination of both methods. The electrodes may besubstituted by any equivalent material capable of conducting electricalsignals through the stimulator interface with the dermal surface of theupper extremity The electrodes may be attached to a control unit 740which could apply electrical stimulation via the electrodes to the softtissue and nerves in the region where the electrode are placed and theregion immediately surrounding. In another variation of the embodiment,several electrodes can be placed to a combination of targeted regions.

A function generator connected to and controlled by the processor mayfunction to modulate electrical stimulation parameters. The functiongenerator is preferably an arbitrary waveform generator that uses directdigital synthesis techniques to generate any waveform that can bedescribed by a table of amplitudes. The parameters are selected from agroup including but not limited to frequency, intensity, pulse width orpulse duration, and overall duration. The outputs preferably have apower limit set by the maximum output voltage. In a preferredembodiment, the digitally stored protocols cycle through variousstimulation parameters to prevent patient acclimation. Variation ofelectrical stimulation is achieved by the function generator.

Optimizing Stimulation: Dephasing

In a preferred embodiment, the stimulation is designed to dephasesynchronicity in the brain. The concept of dephasing the abnormalcircuit follows on recent work showing neural retraining reduces thenetwork's propensity to fall into an abnormal rhythm. Interestingly,movement disorders are often associated with abnormal periodicsynchronous firing in brain circuits. In Parkinson's disease, thiscircuit is in the basal ganglia. In ET, it is the olivo-cerebellarcircuit. These anomalous oscillations are thought to drive the tremor,as supported by numerous studies showing that the tremor observed in thehand and forearm muscles is synched with pathological rhythmicdischarges in the brain. Recent DBS studies have shown that low-voltagephase-shifted bursts on adjacent pairs of electrodes (called CoordinatedReset) can reduce synchronization in abnormal brain networks and thatthis reduces Parkinsonian tremors. The application of Coordinated Resettheory to treat tinnitus supports the concept of using synapticexcitation to retrain neural networks.

The device disclosed herein offers several advantages overhigh-frequency TENS stimulation, including using lower power (leading toextended battery life, less discomfort from motor recruitment andcontraction, less discomfort from sensory excitation), less suppressionof firing in activity in adjacent nerves (by depletion or othermechanisms), and maintaining longer-lasting effects such that the deviceonly need be used intermittently to train or maintain training of theneural circuit dynamics. The device stimulates sets of nerves in such away that it targets neural subpopulations to reduce synchronization ofthe population. For example, this may be achieved by stimulatingdifferent fingers on the hand. FIG. 8A is a diagram showing a preferredembodiment of the device, in which (810) anode and (820) cathodeelectrode pairs on the fingers are used to excite the branches of theproprioceptive nerves (the median, radial and ulnar nerves) in eachfinger. This arrangement of anode (distal) and cathode (proximal) isdesigned to induce a nerve pulse traveling towards the brain. The uniquestimulation pattern on each finger will send a unique signal to aspecific subpopulation of neurons in the brain because of thesomatotopic organization of the brain, in which signals from differentadjacent or nearby body parts synapse at nearby locations in the brain.In an alternative embodiment, the anode and cathode position may bereversed to inhibit the passage of sensory impulses towards the brain(antidromic collision). FIG. 8B shows an alternate arrangement, in whichthere is only a (830) single electrode on the finger and the (840)second electrode is positioned on the wrist. It will be appreciated byone skilled in the art that the fingers represent only one possible setof targets and different locations may similarly be used target adjacentsubpopulations of neurons. In the alternative embodiment shown in FIG.8C, the electrodes are positioned on different locations on the wrist totarget the (850) median, (860) ulnar and (870) radian nerves. It will beappreciated by one skilled in the art that the input may also bepositioned on other locations or branches of the nerves that input intothe abnormal brain circuit. The location may be on the same or oppositeside of the limb with tremors. The location may be on the surface of theskin, crossing the skin, or implanted. FIG. 8D illustrates variousstimulation sites which can be subjected to stimulation that is delayedor offset by a predetermined fraction or multiple of the tremor period,T, as shown for example in FIG. 9.

The device uses stimulation schemes designed to dephase, override orobscure the abnormal network. FIG. 9A is a conceptual diagram showing asample excitation scheme to dephase brain regions receiving sensoryinput from two sites. For example, the two sites could be two of thefingers shown in FIGS. 8A-8D. The stimulation at site 2 is delayed aftersite 1 by time T/2, where T is the period of the native tremor. Forexample, if the tremor is at 8 Hz the period is 125 ms and thestimulation of site 2 would be delayed by 62.5 ms. The stimulation isdesigned to reset the phase of the neuron, which may be implementedusing high frequency stimulation (above 100 Hz) or a DC pulse. FIG. 9Bis a conceptual diagram showing a sample excitation scheme to dephasebrain regions receiving sensory input from four sites, with subsequentsites delayed by T/4. In another embodiment, the stimulation atdifferent locations is variable in parameters other than timing such asfrequency or pulse width, or a combination of these. These variationsare similarly designed to retrain the brain by dephasing, overriding orobscuring the abnormal network dynamics. In yet another embodiment, thestimulation may occur at a single location but vary in parameters overtime. For example, it may vary in frequency every few seconds or turn onand off. In yet another embodiment, the stimulation is constant and at asingle location. In preferred embodiments of these, the location is atthe median nerve close to the wrist.

Optimizing Stimulation: Sub-Sensory

Stimulating at intensities below the sensory threshold will avoid thediscomfort (tingling, numbness, pain) that can be associated withperipheral nerve stimulation. Because the exact electrode position, sizeand surface contact have a large effect on the stimulation level and theanatomical structures that receive the stimulation, the sensorythreshold may needed to be calibrated for each patient and even for eachsession. This calibration may be done by the user manually setting thestimulation parameters or otherwise indicating their sensory threshold.Another possible mechanism is for the device to automatically sweepthrough a range of stimulation parameters and the patient chooses themost comfortable set of parameter values. Another possible mechanism isfor the patient to choose from among a set of previously chosenparameter values that provided effective and comfortable stimulation. Insome embodiments, the electrode pad can include a topical analgesic,such as Lidocaine, to reduce the discomfort from stimulation, therebyincreasing the sensory threshold tolerated by the patient. In someembodiments, the topical analgesic can be delivered using a controlledrelease formation to provide pain relief for the duration the electrodepad is to be worn, which can be days, weeks or months. Such a method mayprovide more comfort or greater therapeutic effect, due to greaterstimulation intensity and/or synergistic effects with the topicalanalgesic, which can reduce tremor in some patients.

Optimizing Stimulation: High Frequency

Alternatively or additionally, the stimulation waveform may be very highfrequency, typically in the kHz and above, such that the stimulation isnot felt by the user, or it is felt very little. Very high frequencystimulation is thought to make a conduction blockade. However, prior tothe blockade there is an onset response including a strongdepolarization of the nerve. To effectively implement very highfrequency stimulation without causing discomfort for the patient, itwould be preferable to eliminate this onset response. This can be doneby cooling the nerve during the initial stimulation. Motor nerves aregenerally excited by stimulation at about 15 Hz and below, while sensorynerves are generally excited by stimulation at about 50 Hz and above. Insome embodiments, it may be desirable to specifically stimulate abovethe 15 Hz threshold of motor neuron stimulation to avoid causing musclecontraction.

Optimizing Stimulation: Triggered

Alternatively or additionally, triggering the stimulation to the phaseof the tremor can improve effectiveness. The goal of such stimulation isto break the rhythmic entrainment of motor units. More effectivetreatment may permit stimulating at lower levels to achieve similartherapeutic benefits with less discomfort. Essential tremor isessentially a problem of feedback in a resonant circuit. Stimulationtimed off-phase from the tremor may reduce the tremor by altering thecircuit dynamics, for example by shifting the gains on the feedbackloop.

As shown in FIG. 10B, bursts of high-frequency stimulation may be timedto occur when the wrist is at its maximum flexion or extension (FIG.10A). In example (FIG. 10C), the bursts have been shifted to a randomphase. The position of the hand (FIG. 10A) may determine the optimalstimulation duty cycle and timing, such as (FIG. 10B) stimulatingoff-resonance with the maximum tremor deviation or (FIG. 10C) usingbursts of variable temporal delays to avoid resonance with the tremor.

Alternatively or additionally, the stimulation may be chaotic orvariable. The goal of chaotic, random or variable stimulation is toprevent habituation and reduce resonance in the circuit. For example,this may be implemented by varying the stimulation frequency over timeand/or by superimposing higher and lower frequency components, asillustrated in FIG. 11.

Alternatively or additionally, the stimulation may be high frequencyalternating current. This has been shown to block action potentials asthey transmit along axons and could adjust circuit dynamics.

In some embodiments, the stimulation parameters as described above canbe cycled according to a predetermined order to determine the optimalstimulation parameter. In some embodiments, the effectiveness of thestimulation parameters can be monitored over time to determine whether aparticular set of stimulation parameters is losing effectiveness. Insome embodiments, when the effectiveness of a particular set ofstimulation parameters has been reduced by a predetermined amount, thestimulation parameters can be altered or cycled according to apredetermined order. For example, if stimulation is being triggered tothe phase of the tremor, the stimulation can be delivered with random orvariable temporal delays, or if the stimulation was using a setamplitude and/or frequency, the stimulation can be changed to a chaotic,random or variable modality to prevent or disrupt habituation. In someembodiments, the random or variable type stimulation parameters can beutilized according to a predetermined routine, such as daily for apredetermined number of hours, or weekly for a predetermined number ofdays, or at some other predetermined interval including time of day.

Effector: Vibrotactile Stimulation

The effector may be mechanical excitation of the proprioceptors by meansincluding vibrotactile or haptic sensation. The mechanical stimulationmight include force, vibration and/or motion. The effector inducesaction potentials in the target nerves by exciting the Golgi tendonorgans (GTOs) or Pacinian corpuscles. Mechanical effectors can include,for example, small motors; piezoelectrics; one or more vibrotactileunits comprised of a mass and an effector to move the mass such that avibratory stimulus is applied to the body; an eccentric mass mounted ona shaft such that a vibratory stimulus is produced when the shaft isrotated; or an ultrasonic motor but can alternatively be amagnetorheological fluid (MRF) effector or electroactive polymer (EAP)effector.

The vibratory stimulus is optimally 250 Hz, corresponding to the optimalsensitivity of the Pacinian corpuscles (also known as lamellarcorpuscles). The Pacinian corpuscles are the nerve endings in the skinthat sense touch and vibration. Deformation of the corpuscle openspressure-sensitive sodium ion channels to cause action potentials.Alternatively, the vibration may be below 50 Hz to excite the Meissner'scorpuscles (also called tactile corpuscles) in the fingers that aresensitive to light touch.

This mechanical-type stimulator may function to reduce tremor throughseveral methods. One method may be to transmit proprioceptive signals tothe brain that obscure or modify the driving proprioceptive signaltransmitted from the tremulous muscles. Another method may be impedancecontrol. Joint impedance may altering co-contracting muscles throughtranscutaneous neurostimulation, affecting the stiffness of muscles andconsequently muscle contractions. Another method may be the generationof compensatory muscle contractions, through neurostimulation, thatoppose the tremulous contractions. The stimulator is preferably affixedfirmly against the dermal surface, for example through an elastic orVelcro band.

Effectors: Chemical, Thermal & Other

The examples herein have primarily described the stimulation aselectrical or vibrotactile. However, stimulation may alternately beachieved using other effectors that may offer significant benefit interms of patient comfort, portability, safety or cost.

In another variation of the embodiment, the effector may be aneuromodulating chemical that either raises or lowers neurons firingthresholds. The chemical used in the invention may be a topicalanesthetics including, but not limited to the “caine” family. The“caine” family of anesthetics may include but are not limited tobenzocaine, bupivacaine, butacaine, carbisocaine, chloroprocaine,ciprocaine, dibucaine, etidocaine, heptacaine, levobupivacaine,lidocaine, lidocaine hydrochloride, mepivacaine, mesocaine, prilocaine,procaine, propanocaine, ropivacaine, and tetracaine. Other chemicalfamilies may include those of menthol family, or alpha-hydroxy sanshoolfrom Szechuan peppercorn, or capsaicin, all of which are known toinfluence peripheral sensory nerves.

FIG. 12 shows a chemical stimulator that may deliver chemical stimulustransdermally through a patch or could be delivered by microinjection.The preloaded protocols may preferably be predetermined compositions ofthe one or more chemicals. The topical anesthetics in this invention maybe known for other indications and the recommended doses for simulationhave been tested and approved for treatment of other indications. Forexample, the topical anesthetic lidocaine may be administered at 2-10%by weight. Alternatively, lidocaine may be administered in conjunctionwith other anesthetics. As seen in FIG. 12, the two neuromodulatingchemicals are mixed to provide a tailored composition. The chemicalstimulator may be administered as a composition comprising lidocaine2.5% and prilocaine 2.5% by weight. Alternatively, the chemicalstimulator could be administered as a composition comprising lidocaine0.1-5% and prilocaine 0.1-5% by weight.

The chemical stimulator may be alpha hydroxy sanshool from Szechuanpeppercorn. The alpha hydroxy sanshool may be contained in an excipientor carrier. The excipient may include gels, creams, oils, or otherliquid. If the method of delivery is a transdermal patch, theformulation of the chemical agent may preferably be a cream or gel. Thecomposition can be selected by the user through the control module 740(of FIG. 7). If the method of delivery is microinjection, theformulation may preferably be a solution.

In some embodiments, the effector can be a temperature effector 732 (ofFIG. 7) that induces cooling or heating. The effector may modulateneuronal firing by directly cooling the nerve or indirectly by coolingadjacent muscle, skin or other component of the arm. A temperatureeffector can include, for example, piezoelectrics (e.g. Peltier coolingtiles), circulating fluid, compressed expandable gas, cooled or warmedsolid material or evaporative material. One example of a coolingeffector can be as disclosed in U.S. Publication No. 2010/0107657, whichis incorporated herein by reference. Heating or cooling may be appliedas a patch that adheres to the dermal surface, by attachment to affixthe stimulator to the dermal surface, such as an armband, or by animplant.

In an embodiment with a thermal stimulator, the preloaded protocols maypreferably be predetermined temperatures of stimulation and associateddurations of stimulation. Preferably, a preloaded protocol may call forthermal cooling for the duration of 15 minutes and cooling temperaturesin the range of 15-25° C. The duration of stimulation may bepreprogrammed to (but is not limited to) approximately 5 minutes to 30minutes. The maximum length of stimulation should be well tolerated bythe user and not cause any muscular or neurological damage. Temperaturesensors may function to detect the effective cooling temperature in anembodiment where the stimulator is a thermal stimulator. Effectivecooling or heating temperature may be the temperature felt by the user,and this is not necessarily the same as the applied temperature. If thetemperature sensors determine that the effective temperature reaches athreshold, which may range from 5 degrees C. greater or less than theapplied temperature for a particular protocol, the processor 797 (fromFIG. 7) may modify said protocol to cool or heat more than originallyprogrammed to compensate for the discrepancy between effective andintended cooling.

The invention may alternatively apply other effectors including acoustic(using ultrasonic excitation for exciting sensory nerves at thefingertips), vibratory, tactile, luminescent (e.g. light exposure inoptogenetically modified nerves), magneticically (e.g. by rapidlyswitching RF fields) or a combination of mechanisms.

Form Factors: General Wearable Stimulator

Referring to FIG. 14A-E, the system 700 from FIG. 7 can be non-invasive,fully implantable, or partially implantable. For example, a non-invasiveembodiment can include a non-invasive housing such as a sleeve 1400, ora patch 1410, or a glove. In such non-invasive embodiments, theinterface of the housing is in communication with an external part ofthe patient. In some embodiments, one or more of the system componentscan be implanted 1420. For example, an effector and/or at least aportion of the housing interface can be implanted in the patient at apoint of contact while the power source is external to the patient.

A non-invasive system housing can facilitate in maintaining theinterface and/or effector in close proximity to the patient. The sleevecan cover a long stretch of arm or be a narrow band. The sleeve cancover at least a portion of the circumference of any part of a limb orthe sleeve may cover the full circumference of any part of the limb. Thefunction of the sleeve may be to maintain the position of the externaldevice relative to the implant. The purpose of maintaining the positionmay include achieving good power transfer, reliable communication orother purposes.

The housing may be made of any material suitable to achieve the desiredproperties. For example, the housing material may be flexible and/orstretchable material, polymer or fabric. The housing can includefasteners such as Velcro, laces, toggles and/or ties to secure thedevice to the patient. The housing can include multiple layers and/orpockets configured to hold various components of the system as disclosedherein.

The system may be positioned by the patient with or without theassistance of a caregiver. In some embodiments, the system may haveassistive mechanisms to position it on the arm, such aspressure-responsive snaps and/or self-aligning magnets. In someembodiments, such as sleeve 1400, the system may be slipped on (similarto a sports sleeve) over the end of a limb or wrapped around the arm orself-wrapped around the arm (similar to a snap-band). In someembodiments, the housing may be in the form of a patch 1410. Forexample, a housing patch 1410 can be secured to the patient's skin usinga removable or degradable adhesive. The patch may be worn for a varietyof times, including but not limited to patches worn only during theperiod of stimulation and patches left in place for several days, weeks,or months. The patch may also be attached mechanically, chemically, orelectrically. Such embodiments include but are not limited to staples,strings, or magnets that secure the patch in a desired place.

In some embodiments, the non-invasive system can include an interface,which is in communication with the patient, but where the housing is notattached to the patient. For example, the system can be an externaldevice with which the patient interacts. For example, the housing mightbe an open or closed tube-like structure in which the patient can placea limb. As illustrated in FIG. 14D, another example includes an externaldevice that resembles a pad 1430 or support structure, such as a wristpad or support, over which a patient can place at least a portion of alimb.

In one embodiment, the housing 1450 may have the configuration of awristwatch as shown in FIG. 14H-L worn on the wrist or arm of the user.The housing 1450 may contain an interface 1452 separated, partiallyseparated, or connected to the housing, and which may interact with theuser. The interface 1452 may connect to the housing 1450 and bedisposable after use for a period of time. The electrodes 1454 of theinterface may be arranged in strips and may be arranged in anode/cathodepairs. Other electrode configurations as described herein may also beused. The period of time may be after a single use, or after multipleuses over the period of minutes, hours, days, weeks, or months. Theinterface itself may be the entire portion that is the wristband or maybe a portion of the wristband or be attached to the wristband. Thewristband itself can be part of the interface or be part of the housing,or both. In one example, the wristband with or without the interface maysnap around the wrist, by including a feature of elastic material thatis slightly curved so that when moved, the wristband wraps into acircular shape around the wrist. In another example, there is atemperature sensitive material, like nitinol, that has shape memory, sothat when the device comes into contact with skin, the wristband with orwithout the interface may change shape to wrap around the patient'swrist. In another example, the wristband with or without the interfacehas one or more metal wires inside or outside the wristband that retainsa new shape when moved to allow the user to place the device on thewrist and add force to shape the wristband onto the user's uniqueanatomy. In another example, the wristband with or without the interfacewraps partially or completely around the wrist. This wrap may be in thesame axis, or may be a spiral wrap.

The disposable or non-disposable interface may be connected to thehousing in a number of different ways, including but not limited tosnapping features, velco, pressfit, magnets, temperature, adhesive, thatmay or may not include self aligning features. The connection may be inone or more multiple dimensions or axes. As an example, FIGS. 14J-14Lshow one potential embodiment where there is a self aligning piece, thatcan be a magnet, that connects the interface to the body in 3dimensions. The circular shape of the aligning piece may allow the firstdimensional alignment in one plane. The bar shape portion of thealigning piece, which can be offset from the circular feature of thealigning piece, may align the interface in the proper axis. The overallshape of the aligning piece can align the interface in the finaldimension, which in this particular example of embodiment is the depth.The housing can have a matching feature of this shape for which theconnection can connect to. It is possible that the connection featurecan be reversed and the aligning piece be placed on the housing, and thematching feature of shape be placed on the interface. These connectionsof the aligning piece can possibly have or not have magnets on one, bothor none of the housing or interface components.

Alternatively, the external device may be an object not worn on thebody. For example, it may have the form factor of a cellphone and thepatient would carry the device around in their pocket, bag, hand orother ways that cellphones are transported and supported, such as on atabletop. It may be designed to sit on a furniture surface in thelocation where the patient wants their tremor controlled, such as at thedining room table, in the kitchen, or in their dressing room.

As shown in FIG. 14M, another preferred embodiment of the invention maycomprise a stimulation device with one or more electrodes 1460 appliedalong the spine. The stimulation device may function to stimulate therelease of neurotransmitters and reduce tremor through neuromodulationof the nerves located along the spine. Stimulation may affect therelease and uptake of neurotransmitters, thereby affecting the nervesinnervating the tremulous regions. The electrodes are preferably placedon the dermal surface at the cervical spine roots, preferably from C1 toC8 but most preferably between C5 and C8. The electrodes are preferablypatch electrodes. The operating unit is preferably affixable to the userand the leads connecting the electrodes to the operating unit arepreferably magnetized for easy connection. The operating unit may beconnected to and controlled by the processor. Since the electrodes arepreferably placed along the spine (back side of the user), a detachedand portable controls module may be more convenient for a user tooperate.

In one embodiment the electrodes may be placed on either side of thespine around C2 to C8 region of the neck and shoulders. The electrodesmay be placed approximately 100 cm to 1 cm away from the spine, and maybe placed 200 cm to 5 cm apart from each other. The stimulationparameters may include a phase duration of between 500 and 30 μseconds,which may preferably be 300-60 ρseconds (micro-seconds). The pulse ratemay range from 10 Hz to 5000 Hz, and the preferable range may be 50 Hzto 200 Hz, or 150 Hz. The cycle time may be continuous, or may rangefrom 5 seconds to 1 hour. The preferable cycle time may be approximately5 seconds to 20 seconds, or 10 seconds. The duration of electricalstimulation may range from 5 minutes to 24 hours per day. The preferablerange may include 30 minutes to 60 minutes repeated approximately 10times per day, or the preferable range may be approximately 40 minutesto 1 hours per day and repeated once per week to once every day. Theamplitude (which may be used interchangeably with intensity) may rangefrom 0.1 mA to 200 mA, and a preferable range may include 1 mA to 10 mA.The length of time the user may use the device before having an effecton the user's tremor may be one day to one month, or may preferablyrange from 2 days to 4 days.

Form Factors: For Electrical Stimulation

Conventional TENS devices are often difficult to position, bulky anduncomfortable. The innovations below are solutions to make it easy toquickly apply, adjust a simulator to control ET and to enable patientsto use it discretely and comfortably.

With a conventional TENS device, it is difficult to properly size andposition the sticker electrodes to optimally target the desired nerve.Smaller electrodes increase the current density at the target nerve, butwith smaller pads it is more likely they will miss the nerve, and highercurrent density from smaller electrodes can cause discomfort. Largerpads are easier to position, but need more power and are more likely tounintentionally stimulate adjacent tissues. The following innovationsresolve these challenges and achieve consistent, effective, comfortable,and safe stimulation.

Instead of using only a single electrode as the cathode and a singleelectrode as the anode, the device may contain an array of electrodes1500, as illustrated in FIG. 15A-15C. Although the electrodes are shownindividually on the patient's skin for the sake of clarity, in practicethe array of electrodes can be integrated into a sleeve, flexible pad orsubstrate, or other form factor as described herein. An appropriatecombination of electrodes would be selected each time the device isrepositioned or based off the detected stimulation needs. Thestimulation may use single electrodes as the anode and cathode, or mayuse a combination of electrodes to shape the simulation field. Theelectrode selection may be automatic based on feedback from sensors inthe device (see below). Alternatively, the electrode selection may bedone manually by the user. For example, the user may cycle through theelectrode combinations until they find the combination that providesoptimal tremor reduction or achieves a surrogate for the correctplacement such as tingling in the 1^(st) (index) and 2^(nd) finger asoccurs with median nerve sensory stimulation. FIG. 15A illustrates a twodimensional array of discrete electrodes 1500. Alternatively, some ofthe electrodes can be combined into linear rows, such that the twodimensional array is formed from a plurality of rows of electrodes. FIG.15B illustrates a linear array of electrodes 1500 which can be worn asbands, as shown, or patches, pads, sleeves, and the like. FIG. 15Cillustrates a housing 1502 that can be used to hold the array ofelectrodes 1500.

Alternatively, electrical stimulation from a poorly positioned electrodemay be redirected to the target nerve by modifying the conductionpathway between the electrode and the target nerve. For example, aconduction pathway enhancer 1600, which can be made from a conductivematerial, can be placed on the patient's skin, embedded into the skin,implanted, or a combination of the above, in order to enhance theconduction of the electrical stimulus from the electrode 1602 to thetarget nerve 1604, as illustrated in FIGS. 16A-16D. The conductionpathway enhancer may be placed over the nerve and/or across the nerve.For example, in one embodiments, a tattoo of conductive ink may directoff-target stimulation towards the median nerve. A tattoo moreconductive than adjacent structures (i.e. blood vessels, nerves) willprovide the path of least resistance and redirect the current. To placeor position the conductive tattoo, the target nerve is first positivelyidentified. Then the conductive tattoo is placed over the target nerve.As illustrated in FIGS. 16A-16D, the conductive tattoo may include aplurality of conductive stripes that cross the nerve. In someembodiments, the stripes can be parallel to each other and cross thenerve transversely. In other embodiments, the stripes can be formed intoa star or cross hatch pattern with a center located over the nerve. Inother embodiments, a stripe can also be placed over and parallel to thenerve (not shown).

For user adoption, a wearable device should be discrete and comfortable.In the preferred embodiment shown in FIGS. 14B and 14F, for example, theeffector is electrical and the skin patch has a single electrode orplurality of electrodes electronics printed onto a flexible substrate ina predetermined pattern to make a “second-skin”, similar to a bandaid.For optimal comfort and surface adhesion, the mechanical characteristicssuch as the elasticity and stiffness should be matched to the skin. Thecircuitry and wiring for surface electrical stimulation may be printedor etched into a flexible material such that the device conforms to thebody or to tissue within the body. For example, it may be copper printedon a flexible substrate such as plastic.

In another embodiment as illustrated in FIG. 14G, the device may bepositioned on the surface of the body but containing a transcutaneouspenetrating elements 1470 to improve influence on the nerves. Theseelements may be microneedles, used for improvement of stimulation and/ordrug delivery. In some embodiments, the transcutaneous penetratingelements can form a microelectrode array that is placed on the skinsurface and penetrates through the skin. The microelectrode array canfunction like microneedles, and can both improve signal transmissionfrom the electrode to the nerve and to improve the permeability of theskin to improve topical drug delivery.

Sensors: Types of Sensors

The device or system may include sensors. Sensors for monitoring thetremor may include a combination of single or multi-axis accelerometers,gyroscopes, inclinometers (to measure and correct for changes in thegravity field resulting from slow changes in the device's orientation),magnetometers; fiber optic electrogoniometers, optical tracking orelectromagnetic tracking; electromyography (EMG) to detect firing oftremoring muscle; electroneurogram (ENG) signals; cortical recordings bytechniques such as electroencephalography (EEG) or direct nerverecordings on an implant in close proximity to the nerve. FIGS. 17A-17Bshow representative positions of motion sensors on the (1710) hand or(1720) wrist. Other tracking locations may include the fingers or otherbody parts.

The data from these tremor sensors is used measure the patient's currentand historical tremor characteristics such as the amplitude, frequencyand phase. These sensors may also be used to determine activities, suchas to distinguish involuntary movements (e.g. tremor) from voluntarymovements (e.g. drinking, writing) or the presence and absence of thetremor relative to the time of day or other detected activities such assleep/wake cycles.

The device may also include sensors to provide performance and usagedata, including when the device was worn (e.g. from temperaturesensors), the device's location (e.g. from GPS), battery level, or videorecording. In another embodiment, the sensor is a temperature sensor tomeasure the temperature of a cooled limb. In another embodiment, thesensor includes video recording. In another embodiment, sensors fromexisting hardware such as a smartphone are used. For example, the tremormay be measured using the accelerometers on a smartphone or engaging thepatient in a tremor-inducing writing task by analyzing a line traced ona smartphone screen.

Sensors. Algorithms to Extract Tremors

Algorithms will be used to extract information about tremors from thestream of data provided by the sensors. The tremor may be identifiedbased off its time-domain signal, frequency-domain signal, amplitude, orfiring pattern (e.g. bursts, spikes). For example, in FIG. 18A-18B, thefrequency analysis of the spectral power of gyroscopic motion dataindicates that the tremor is centered at approximately 6.5 Hz (see themaximum power in the lower plot).

Motion data can be taken as each raw sensor channel or by fusing the rawsignals of multiple sensors. As one example, multi-axis accelerometerdata can be combined into a single numerical value for analysis. Thealgorithm will extract motion data in the 4 to 12 Hz range to removemotions that are not attributable to the tremor. This may be done usingany combination of notch filters, low pass filters, weighted-frequencyFourier linear combiners, or wavelet filters. As each patient has adominant tremor frequency, this range may be narrowed based on specificknowledge of the patient's tremor or tremor history. For example, for apatient with a 6 Hz tremor an analysis algorithm may extract only motiondata in the 5 to 7 Hz range. Alternatively, if a patient is known tohave a tremor that flexes and extends the wrist by a maximum of5-degrees then an analysis algorithm would determine that a measuredmotion of 45-degree wrist flexion is likely due to intentional grossmovement rather than tremor. Alternatively, the algorithm will samplethe motion data by identifying time periods likely to correspond topostural holds or kinetic fine motor tasks.

Once the appropriate motion data has been extracted, the algorithm willanalyze key characteristics of the tremor including the amplitude,center frequency, frequency spread, amplitude, phase, and spectralpower.

Sensor fusion techniques can also be used to analyze different aspectsof the tremor. For example, a multi-axis accelerometer and gyroscopeattached to the backside of the hand could be combined to reduce noiseand drift and determine an accurate orientation of the hand in space. Ifa second pair of multi-axis accelerometer and gyroscope were also usedon the wrist, the joint angle and position of the wrist could bedetermined during the tremor. This could isolate what excitations ofwhich nerves are causing damping of the different muscle groupscontrolling the tremor.

ET patients have two components of their tremor. Kinetic tremors arepresent during intentional movement and have a major impact on qualityof life because they impact a person's ability to accomplish daily taskslike drinking, eating writing and dressing. Postural tremors are presentduring static positions held against gravity. They can be embarrassing,though are less impactful on quality of life. Postural tremors typicallypresent earlier in the disease course and are thought to drive kinetictremors. Both components are typically in the range of 4 to 12 Hz, witholder patients experiencing lower frequency tremors.

Detecting postural and kinetic tremors is more challenging thandetecting resting tremors. Resting tremors are present in other movementdisorders including Parkinson's disease and can be easily identified byanalyzing tremors present only while the limb is at rest. Extractingkinetic tremors from motion data is challenging because it is necessaryto separate the motion due to tremor from the motion due to the task.

Identifying postural tremors may be easier than kinetic tremors sinceaccelerometer/gyroscopic data during kinetic tasks are corrupted by themotion involved in the task. It is thought that postural tremors maydrive the kinetic tremors because people often have postural tremorsearlier in life than kinetic tremors and they are about the samefrequency. The correlation of postural and kinetic tremors we discoveredin our clinical study, as illustrated in FIG. 19, supports this theoryof using postural tremor data to analyze or treat kinetic tremors.

Sensors: Data Storage & Usage

As shown in FIG. 20, the stimulation device 2000 can contain hardware,software and firmware to record and transmit data such as the tremorcharacteristics, stimulation history, performance, usage and/or controlof the device to a data portal device 2002, such as a smartphone, cellphone, tablet computer, laptop computer, desktop computer or otherelectronic device using a wireless communication protocol, such asBluetooth.

Data recorded using the device used the ET patients can be stored on asmartphone that transmits it to a cloud-based database/server 2004, orthe device used by the ET patients may directly transmit data to acloud-based database/server 2004, enabling many activities includingtracking tremors, optimizing stimulation, sharing with caregivers andphysicians, and building community. The data may provide information tothe controller, real-time feedback to the patient, caregivers and/orclinicians, or may store the data to provide historical data to thepatient, caregivers and clinicians. The data stored on the cloud 2004can be viewed on multiple platforms 2006 by multiple users 2008. Inaddition, the data on the cloud 2004 can be pooled and analyzed by acomputing device 2010.

Patients are generally monitored for tremor every few months, or perhapsannually, when they visit their physician. This monitoring is typicallyhighly subjective. Further, tremor severity can be dramatically affectedby many factors, including sleep patterns, emotional status, previousphysical activity, caffeine intake, food, medications etc.

Such infrequent and inaccurate monitoring limits the ability ofpatients, their caregivers and physicians to understand the severity andprogression of a patient's ET and the effects of various treatments andbehaviors. These factors can interact with the effects of thestimulation provided by the device, and it can be difficult to detectthese interactions. These interactions could be identified to optimizethe therapy and help patients better understand how their behavioraffects their tremor.

In one embodiment shown in FIG. 21A, the tremor is 2100 monitored usingsensors that may be IMUs, electrodes, or any of the other sensorspreviously discussed. The monitoring may be continuous or duringdiscrete time periods. The data from these sensors is 2110 analyzed toidentify changes in the tremor characteristics (amplitude, frequencyetc.) over time. The results are recorded and 2120 displayed to theuser. The 2110 analysis and/or 2120 display may be done on thestimulation device itself or by communicating either the raw or analyzeddata to a secondary device such as a smartphone or computer.

In another embodiment, 2101 behavioral data may also be collected suchthat the analysis may examine the relationship between the tremorhistory and the user's behaviors. Behavioral data may includeconsumption of caffeine, alcohol, medications and anxiety levels. Thesystem can then alert the patient of the interactions between thebehaviors and the tremor.

In another embodiment in which the device is therapeutic (i.e. if it hasan effector), the 2102 stimulation history may be collected such thatthe analysis may examine the relationship between the stimulationhistory and the tremor characteristics.

The embodiment shown in FIG. 21B adds a 2140 upload to the cloud. Theorder of 2140 upload and 2110 analysis may be swapped such that theanalysis is done on-board prior to upload (not shown). Use of the cloudenables the results to be 2120 displayed to the user on a variety ofnetworked devices including smartphone, tablets, laptops and desktopcomputers; to other users such as 2150 physicians or caregivers; or for2160 pooled analysis across multiple patients.

FIG. 21C shows some of the potential uses of the pooled data, including2170 connecting patients to similar patients based on features such astheir tremor characteristics, geography, age and gender or 2180improving the stimulation algorithms.

FIG. 21D shows how the data monitoring and analysis shown in FIGS. 21A-Cmay be used in a closed loop to adjust the stimulation parameters. Inthis way, the algorithms detect interactions between the variables tooptimize the therapy.

The device may contain closed-loop control of the stimulation toadaptively respond to detected tremor or activity levels. The deviceenables sensation of tremor through an activity sensor, data logging andsystematic adjustment of the stimulation parameters to achieve anoptimal tremor reduction. FIG. 26A is a control diagram showing thebasic components of this detection and response system. The (2650)target defines the intended profile. For example, in ET patient thisprofile may be absence of tremor and in a PD patient this profile may beabsence of tremor or rigidity. The (2670) error between the (2650)target and (2660) detection is fed into the (2680) controller, whichmodifies the (2690) output. The (2680) controller may include aprocessor and memory. In addition to the error and measurements, the(2680) controller algorithms may also input the history of measurements,stimulation and activity into its algorithms. The output (2690) modifiesthe stimulation. If the effector is electrical, this may includemodifying the waveform, frequency, phase, location and/or amplitude ofthe stimulation. In the preferred embodiment (FIG. 15), the devicecontains an array of small electrodes and the output modifies theselection of which electrodes to use as the anode and cathode. Theeffect of the modifications are then (2660) detected by the measurementdevice and the process repeats. The (2660) detection and/or (2690)output modification may occur continuously in real-time, with periodicdelays between predefined times (e.g. hourly or daily), or in responseto a user-generated signal such as a pre-defined sequence of movementsor a button press. Alternatively, the controller may alert the patientto manually modify the stimulation parameters. This closed loop may beused for automatic self-calibration.

FIG. 26B illustrates a control diagram showing the basic components ofthis detection and response system, which is similar to the descriptionshown in FIG. 26A, but now with internally and externally locatedcomponents.

The control could also take into account other patterns in behavior,more like a feed-forward controller 2640. For example, typical patternsin eating times could cause the effector to fire more actively atparticular times to reduce tremor for those activities. Also, the personcould indicate in a schedule, based upon their activities for the day ifthey would like increased treatment at certain periods of time, forexample if they had a speech or other anxiety causing events. This typeof information could also be obtained and learned over time by thecontrol unit. Other data such as sleep, food intake, particularlyalcohol and caffeine consumption, exercise history, emotional status,particularly levels of anxiety, and medication usage collected throughother mobile technologies and applications, such as Azumio, Jawbone,Fitbit, etc., which may be integrated into the cloud-based patientdatabase, as illustrated in FIGS. 20 and 21. The user can be prompted toenter such data, such as taking a photo of a meal to determine fooduptake using an imaging processing application. The database willcombine discrete events (e.g., time and amount of caffeine intake) withtime series data (e.g., tremor measurements). Algorithms will examinethe relationship between patient behaviors, stimulation, and tremor.These will optimize stimulation and alert the patient of the behaviorsthat influence tremor. This will allow for individually optimizedtreatment for tremor and feed forward into the system.

In some embodiments, the user may be prompted at predetermined times bythe device or cell phone to perform a specific task, which may betailored to the type of tremor afflicting the patient, such as holdingthe arm out in a specific posture for ET, or placing the arm in a restposition for Parkinson's. During this time, the sensors can record thetremors. In some embodiments, the patient may additionally oralternatively be instructed to consume caffeine or to record the timeperiod that has elapsed since they last consumed caffeine. This data maybe used to determine how caffeine affects tremor, the efficacy of thetreatment protocol and stimulation parameters, the duration of theeffectiveness, and the like. In some embodiments, the patient can beprompted at a predetermined amount of time after stimulation, such as10, 20, 30, and/or 60 minutes after stimulation. The time can beadjusted depending on measured duration of the tremor reductionfollowing stimulation.

The device will have on-board data logging and may transmit thisinformation to an external data portal device, such as a smartphone orinternet-enabled charge & sync station. This transmission may bewireless or direct. The external device will have greater storagecapacity and allow transmission to a database in the cloud. The externaldevice may analyze this data on-board and present information on ascreen or using indicators such as LED lights, or the data may be shownon the stimulation device itself.

The data in the cloud will be viewable on multiple platforms includingsmartphones, tablets and computers. The data will be viewable bymultiple people including the user, his or her physicians, caregivers orfamily members. This will provide a much more comprehensive picture of apatient's tremor and enable optimization of treatment. In someembodiments, users viewing the data can also add comments and notes tothe data, which can be tagged with the identity of the user making thecomment or note, and the time the comment or note was made. In someembodiments, the ability to make annotations can be restricted to thehealth care providers, such as the patient's physician, and the patient.

In some embodiments, access to the data is restricted to the health careproviders and the patient. Access can be limited by requiring users toset up a secure username and password to access the data. In someembodiments, the patient can also provide others, such as family andfriends, with access to the data.

Algorithms for Optimization:

Our data indicate that stimulation using a TENS device is highlyeffective in some patients, somewhat effective in other patients, andineffective in others. However, optimization of the simulationparameters (simulation intensity, frequency, waveform, duty cycle,phasing etc.) enables the device to achieve the greatest tremorreduction with the most comfort in each patient and allows the device toadjust over time in response to changes in the circuit dynamics, devicepositioning, patient state, etc. FIG. 22 shows a decisionalgorithm/controller for device.

In one embodiment, the optimization algorithm starts by initializing oneor more parameters 2200, which may include stimulus amplitude, expectedfrequency, on-time duration, off-time duration, and expected stimulationeffect delay time. Next, a sensor detects 2202 and records tremorcharacteristics, including tremor amplitude, frequency, phase, and othercharacteristics described herein. The detected tremor characteristics2202 are compared with desired target tremor characteristics 2204, whichmay be no tremor or a reduced tremor. The comparison step 2206 candetermine the error or difference between the detected tremorcharacteristics and the target tremor characteristics, and determinewhether tremor or reduced tremor is present 2208, or in other words,whether the detected tremor meets or exceeds the target conditions. Ifno tremor is detected, or more generally, if a predetermined targettremor condition is not exceeded, then the algorithm loops back to thedetection step 2202. If a tremor is detected, or more generally, if apredetermined target tremor condition is exceeded, then stimulation canbe turned on 2210. Once the stimulation has exceeded the set on-timeduration 2212, then the stimulation is turned off 2214, and thealgorithm proceeds back to the detection step 2202. While stimulation ison, the device can upload the recorded data 2218 to the cloud or anotherdevice for further processing. Once the stimulation has been turned off2214, the algorithm can monitor the off-time duration 2216, and cancontinue to upload data 2218 once the off-time duration has elapsed.Alternatively, data can be uploaded even before the off-time haselapsed. User-reported events 2220, which can include caffeine oralcohol intake, feelings of anxiety, and other events that may affecttremor, can also be entered into the system and sent to the cloud. Thedata can be processed by a controller 2222 which can optimize thestimulation parameters using various algorithms, including machinelearning algorithms. Once the parameters are optimized, the newstimulation parameters are set 2224. A report 2226 can also be sent tothe patient that can highlight or correlate various behaviors identifiedin the user-reported events with measured tremors.

In one embodiment, the stimulation algorithm is designed to optimize thetherapeutic “on”-time. The optimization algorithm may find the bestsolution for outputs including but not limited to controlling tremorduring specific tasks, at specific times of day, in specific location orsimply to optimize the overall daily minimization of tremor. Thealgorithm may be self-calibrating to adjust stimulation parametersincluding but not limited to the frequency, amplitude, pulse width,electrode selection for cathode and anode and/or timing of turning thestimulation on and off. The algorithm may respond user input or may beentirely pre-programmed. The algorithm may be a learning algorithm totailor the stimulation over time to adjust in real-time to a patient'stremor or patient-defined needs. The stimulation may be triggered on oroff in response to inputs including but not limited to user input (e.g.turning the device on or and off), timing since previous use, time ofday, detection of tremor (e.g. by accelerometers), electricalrecordings, or algorithms based on the previously described or otherinputs. As an example, the user can use voice activation to turn thedevice off to utilize the therapeutic window (i.e., the time of tremorreduction after stimulation is turned off) to provide a time interval ofsteadiness needed for intentional movements. In another example, theuser bites down or uses the tongue muscle detected by an external deviceplaced inside or outside the oral cavity, which will signal to turn offthe stimulation and allow the user steadiness of the arm to enableexecution of intention actions with steadiness. In some embodiments, thesystem and algorithm can detect the type of tremor, such asdifferentiating between a postural tremor and kinetic tremor, based onan analysis of the tremor parameters and the measured activity of thepatient. In some embodiments, the stimulation parameters may bedetermined in part based on the type of tremor detected.

In some embodiments, the system can be controlled by an event trigger.Event triggers can include defined movements, temperature, voiceactivation, GPS location, or based on data received by a sensor or anycombination thereof. For example, the device can be turned on or offduring an intentional movement, such as, before a tremor has started orended respectively. In another example, the device is turned on or offwhen a specified temperature is reached. The system may act to achieve adesired tremor suppression profile. For example, the control mayactivate the device during a period of desired tremor suppression; priorto a period of desired tremor suppression, with effects lasting beyondthe use of the device; and/or in response to detection of the tremor.

Optimization Based on Community Data

At present, the time course of tremors is poorly understood. Whilecreating a database for a single patient will improve our ability toreduce tremor in that patient, combining individual patient data into adatabase that includes recordings from many patients enables morepowerful statistical methods to be applied to identify optimalstimulation parameters. In some embodiments, data from patientssuffering from the same type of tremor can be combined. In someembodiments, the tremor data from each patient can include searchableand sortable metadata that allow the collection of data in the databaseto be sorted, searched and/or reorganized on demand. The metadata caninclude type of tremor (tremor amplitude, tremor frequency, temporalpresence of tremor etc.), name, age, race, sex, location, time, food anddrink consumption (particularly for caffeine and alcohol), activityhistory (exercise, sleep etc.), medications, past treatments, andcurrent treatments.

The systems described above with respect to FIGS. 20 and 21 can beadapted to data from many patients going into a database, and thealgorithms can operate on the massive set of data.

Community Building

Individuals with ET feel isolated by the disability associated withtheir tremor. Asa result, they are highly motivated to meet other peoplewith ET. There is an active and growing set of support groups thatorganize meetings and enable patients with ET talk about their issuesand discuss possible solutions. Attending these meetings can bechallenging because some patients with ET have difficulty driving. Also,the individuals within a particular physical location who attend asupport group may have symptoms that are different from each other, andthey lack the ability to identify other patients that are most like eachother.

Algorithms can help individuals find members of the ET community thathave similar profiles. For example, algorithms can characterize patientsbased their age, tremor severity, tremor features, success withtreatment, treatment type, medication type, location (based on addressor GPS), and other characteristics. This will help them communicate witheach other and to share information from the central community websitethat is customized to a particular individual with ET or a caregiver.For example, system can identify patients within a geographical locationor identify other patients within a predetermined distance from aparticular patient. Patients may have the option of joining an online ETcommunity and making their location searchable on the system. The systemmay identify to a patient existing ET community support groups within apredetermined distance.

Other Processor Library. Data Storage:

The processor 797, as illustrated in FIGS. 7A-7D for example, mayfunction to operate on data, perform computations, and control othercomponents of the tremor reduction device. It may preferably be amicroprocessor with peripherals or a microcontroller. For example, theprocessor could receive input from the user via the controls module 740and could control the execution of stimulation as selected by the user.In another embodiment, the processor 797 could execute predefinedstimulation protocols selected by the user. These stimulation protocolscould be found in the digital library of stimulation protocols 798,which may be loaded in the processor 797 or stored in external memory,like an EEPROM, SD card, etc. The processor 797 can also receiveinformation from the sensors 780 and process that information on boardand adjust the stimulation accordingly. The selection of the processoris determined by the degree of signal processing it needs to do and thenumber and type of peripherals it needs to control. Communication withperipherals can be executed by any of the well-known standards such asUSB, UART, SPI, I2C/TWI, for example. The processor may also communicatewirelessly with other device components using Bluetooth, Wifi, etc. Theprocessor may be on board the device, or the tremor data be transmittedvia a wireless link between the processing unit and the stimulationunit.

In an embodiment with an electrical stimulator 730, the preloadedprotocols 798 may be electrical stimulation or a sequence of electricalstimulations. Electrical stimulation or electrical signal refers to anelectrical pulse or pattern of electrical pulses. The electricalstimulation may include parameters such as pulse frequency, amplitude,phase, pulse width, or time duration of electrical stimulation. Theseparameters may be predefined or controlled by the user.

The data storage unit 770 may function to store operational statisticsabout the device and usage statistics about the device, preferably inNAND flash memory. NAND flash memory is a data storage device that isnon-volatile, which does not require power to retain the storedinformation, and can be electrically erased and rewritten to. In somecases, it may be beneficial to have this memory be removeable in theform of a micro-SD card.

Power:

The effector may be electrically coupled to one or more power sources,as illustrated in FIGS. 7A-7D for example. The power source 750functions to power the device. The power source 750 may be connected tothe processor 797 and provide energy for the processor to run. The powersource may preferably be rechargeable and detachable as this allows thedevice to be reused. The power source may preferably be a battery.Several different combinations of chemicals are commonly used, includinglead-acid, nickel cadmium (NiCd), nickel metal hydride (NiMH), lithiumion (Li-ion), and lithium ion polymer (Li-ion polymer). Methods ofrecharging the battery are preferably attaching to a wall socket orother powered device, solar power, radio frequency, and electrochemical.An alternative source of power is ultracapacitors. Ultracapacitors maybe divided into three different families—double-layer capacitors,pseudocapacitors, and hybrid capacitors. Ultracapacitors may preferablybe made with nanoporous material including activated charcoal, graphene,carbon nanotubes, carbide-derived carbons, carbon aerogel, solidactivated carbon, tunable nanoporous carbon, and mineral-based carbon.Ultracapacitors provide an advantage of faster charging than batteriesas well as tolerance of more charge and discharge cycles. Batteries andultracapacitors could alternatively be used in conjunction as thetolerance of ultracapacitors to a large number of charge-dischargecycles makes them well suited for parallel connections with batteriesand may improve battery performance in terms of power density.Alternatively, the power source may harness energy from the body. Insome embodiments the power can be harnessed by kinetic motion, bythermal energy, and/or by sound. The power source may alternativelyinclude a plug to an external source, such as a general appliance.

In one embodiment, a special charging station or dongle could be used torecharge the device. The benefit of the special charging station is thatit could also facilitate the upload of data from the device to the webvia Wifi or another communication protocol.

Implants:

In some embodiments, at least a portion of the system is implantable. Animplanted stimulator may offer greater control and comfort than surfacestimulation because it is located closer to the nerve and avoidsexciting cutaneous afferents.

The method of stimulating peripheral nerves to control hand tremorsintroduces specific requirements for an appropriate implantedstimulator. First, the implant should be small to minimize theinvasiveness of the procedure used to position the implant and make itappropriate for implantation. Second, because the stimulation may beresponsive to the detected tremor or user input, the implant should becapable of receiving communication from an external device. Third, thedevice should tolerate variability in the positioning of the externaldevice.

Any number of the system components disclosed herein can be implanted.In some embodiments, the housing, interface, effector and power sourceare implanted and the controller is external to the patient. In suchembodiments, the controller, may be, for example, in wirelesscommunication with the effector. In other embodiments, the power sourceis external to the patient.

The device may be implanted subcutaneously, partially implanted, or maybe transcutaneous (passing through the skin), may be on the surface ofthe skin or may not be in contact with the body. It may be an assemblyof these devices, such as a surface component that communicates with orpowers an implanted component. If it is implanted, the device may beimplanted in or around nerves, muscle, bone, ligaments or other tissues.

In one embodiment, the implant is positioned in or near the carpaltunnel to influence the nerves passing through the carpal tunnel. Inanother embodiment, the implant is positioned on or near the mediannerve in the upper arm between the biceps. In another embodiment, theimplant is positioned on or near the median, radial or ulnar nerve inthe forearm or wrist. In another embodiment, the implant is positionedon or near the brachial plexus to influence the proprioceptive nervespassing from the arm toward the central nervous system.

The implanted portions may be placed or delivered intravascularly toaffect nerves in the area within range of the implant's effect. In oneexample, a device is placed in or through the subclavian artery or veinto affect the nerves of the brachial plexus.

As shown in FIG. 23, a preferred embodiment of a controllable device fora user to reduce essential tremor comprises electrodes 2310 made frombiocompatible materials implanted at least partially sub-dermally tostimulate targeted nerves: an external operating unit 2320, whichcontains a user controls interface, connected by leads to the implantedelectrode 2310. The device may contain further elements which mayinclude a processor 797 that performs computations and controls othercomponents; a processor controlled function generator; a digital library799 stored on the processor or memory which contains preloadedmodulation protocols; a sensor 780 connected to or in communication withthe processor 797 which detects predefined parameters and transmits thatparameter information to the processor; a data storage unit 770connected to the sensor and processor; and a power supply 750.

In this embodiment, the implanted electrodes 2310 may function toprovide direct electrical stimulation to the targeted nerves. Since theelectrodes are implanted at least partially into the body and willremain an extended period of time (preferably several years), theelectrodes may be made of material that has suitable electricalproperties and is biocompatible. The electrode 2310 material ispreferably selected from a group including silicones, PTFE, parylene,polyimide, polyesterimide, platinum, ceramic, and gold, or of naturalmaterials such as collagen or hyaluronic acid. The electrodes 2310 canbe of varying shape and size but importantly contact the nerves ofinterest. Electrode shapes include planar shanks, simple uniformmicrowires, and probes that taper to a thin tip from a wider base. Theelectrode may have a proximal end and a distal end. The distal end, maycontact the nerves, and be adapted to deliver neural stimulation pulsesto the selected nerves. The proximal end of the lead may be adapted toconnect to the external operating unit run by a processor 797.

In a variation of the embodiment, there may be multiple leads connectedto different nerve bundles. In another variation, there may be wirelesscommunication with the implant as shown in FIGS. 24A-24D. The implant2400, which can be a microelectrode or microstimulator, can be insertedproximate the nerve using needle insertion. The needle 2402 can beinserted into the patient next to or near the target nerve 2404, andthen the implant can be ejected from the needle. The implant 2400 can bein communication with, transfer and receive data with, and be powered byan externally located device 2406, such as a decision unit describedherein.

In one embodiment, the Interface may be an implanted nerve cuff. Thecuff may either fully or partially encircle the nerve. The cuff may beattached to the nerve by means of closing butterfly arm electrodes. Inanother embodiment, the Interface may be a nerve abutment. The abutmentmay be in close proximity to the nerve or may lie along the nerve. Thefunction of the cuff may be to provide good contact or close proximitybetween the device and the nerve. In another embodiment, the Interfacemay be anchored on the nerve or sheath around the nerve. For example,the device may be wrapped around, tied to, clamped to, tethered withsmall barbs to or chemically fused to the nerve or nerve sheath. Thefunction of the cuff, coil, abutment or anchor is to provide goodcontact or close proximity between the device and the nerve. Some ofthese embodiments are depicted in FIGS. 25A-25F.

For example, FIGS. 25A-25C illustrate an embodiment of a coil electrodeinterface, which can be a multi-coil electrode, as shown, or a singlecoil electrode. In some embodiments, the coil electrode 2500 can be madeof a shape memory material, such as nitinol, and can have a relaxed,straight configuration before insertion and implantation, and a coiledconfiguration after exposure to body temperature. FIGS. 25D and 25Eillustrate embodiments of butterfly cuff type electrodes 2510, which mayat least partially encircle the nerve. As in other embodiments, theinterface can include single or multiple electrodes, and can befabricated from a shape memory material to have an open configurationduring delivery and a closed configuration wrapped around the nerveafter implantation. FIG. 25F illustrates an embodiment of an interfacehaving a linear array of electrodes 2520 that can abut against and liealong the nerve.

The method of inserting the implant may involve local or generalanesthesia. The implant may be delivered through one or more puncturesin the skin, such as a needle or suture, or it may be an open incisionmade in the skin to access the target area, or it could include bothmethods. In one embodiment, the device may be implanted by threading allor part of the device around the nerve and or surrounding tissue, suchas blood vessels or tendons.

In one embodiment, the implant may include two electrodes positionedalong a vascular pathway. The pathway may be along the palmar arch andthe electrodes may be positioned in the brachial and axillary arteries.The fluid column between the electrodes may carry electricity andstimulate adjacent nerves. The electrodes may be either internal to thevascular pathway, like a stent, or external to the vascular pathwaysimilar to a vascular wrap. In one embodiment, the device may be animplant capable of two-way communication with an external device. Theembodiment may contain memory. The external “listener” device may alsobe a power source. The implant could communicate information such as itspower reserves or usage history to the “listener”. In anotherembodiment, the device is an implant capable of sensing activity on thenerve or adjacent nerves and reporting this information to the listener.

In another embodiment, the device or devices used to place the devicemay use ultrasound for guidance. Ultrasound may be used to measureproximity to blood vessels, nerves or other tissues, or to characterizethe type and location of adjacent tissues.

In another embodiment, the electrodes for stimulation may be injected asa liquid. In another embodiment, the electrodes may be flexible anddelivered in a viscous medium like hyaluronic acid. In anotherembodiment, the electrodes may be made of nitinol that takes its shapeat 37 degrees Celsius. This would permit injecting or inserting theelectrodes in one configuration, such as an elongated configuration tofit in a needle, and then would take their form when warmed to bodytemperature. Some of these examples are depicted in FIG. 25.

The implant may contain the necessary components for uni-directional orbi-directional communication between the implant, an external powertransmission, a communication system, and/or electronics to storeprogrammable stimulation parameters. The device may contain a wirelessmicromodule that receives command and power signals by radiofrequencyinductive coupling from an external antenna. If the effector iselectrical, the incoming communication channel may include informationincluding the stimulation frequency, delay, pulsewidth and on/offintervals.

Transcutaneous charging or powering reduces the implant size byeliminating the need for a large power source (e.g. battery) andeliminates the need to replace the power source with repeat surgeries.An external component may be used to wirelessly power the internalcomponent, such as by radiofrequency (RF) power transfer. For example,the external device may emit RF power that the internal componentreceives with a resonant coil. The power may be transmitted at a varietyof wavelengths, including but not limited the radiofrequency andmicrowave spectrums, which range from 3 kHz to 300 GHz. Alternatively,the internal device may contain a battery. The external device may beworn or carried on the body, or it may be in the nearby surroundingssuch as on a nearby table or wall. It may be portable or fixed. Thedevice may contain a capacitative energy storage module electrode thatstimulates when it discharges. The electronics may be significantlysimplified if the powering itself drives the stimulation profile. Thecapacitor blocks direct current while allowing alternating current topass. When the capacitor reaches its dielectric breakdown, it dischargesand releases a stimulation pulse.

The implant may also sense the tremor directly, such as by usingelectroneurography (ENG) or electromyography (EMG) signals or anaccelerometer or a combination of the above. In this case, the implantmay include multiple electrodes since microelectrodes andmacroelectrodes are preferable for sensing and stimulating,respectively. The device may also include an outgoing communicationchannel to communicate the detected events.

Various embodiments of a tremor altering device and methods for using ithave been disclosed above. These various embodiments may be used aloneor in combination, and various changes to individual features of theembodiments may be altered, without departing from the scope of theinvention. For example, the order of various method steps may in someinstances be changed, and/or one or more optional features may be addedto or eliminated from a described device. Therefore, the description ofthe embodiments provided above should not be interpreted as undulylimiting the scope of the invention as it is set forth in the claims.

Certain features that are described in this specification in the contextof separate embodiments also can be implemented in combination in asingle embodiment. Conversely, various features that are described inthe context of a single embodiment also can be implemented in multipleembodiments separately or in any suitable subcombination. Moreover,although features may be described above as acting in certaincombinations and even initially claimed as such, one or more featuresfrom a claimed combination can in some cases be excised from thecombination, and the claimed combination may be directed to asubcombination or variation of a subcombination.

1-19. (canceled)
 20. A method for transcutaneously stimulating afferentperipheral nerves of a stroke patient, the method comprising: measuringone or more characteristics of a tremor of the patient using one or morewearable sensors; analyzing data from the one or more wearable sensorsto calculate a fraction of a period of the tremor; positioning a firstperipheral nerve effector on the patient's skin to stimulate a firstafferent peripheral nerve; positioning a second peripheral nerveeffector on the patient's skin to stimulate a second afferent peripheralnerve; delivering a first electrical stimulus to the first afferentperipheral nerve through the first peripheral nerve effector; anddelivering a second electrical stimulus to the second afferentperipheral nerve through the second peripheral nerve effector, whereinthe second electrical stimulus is offset in time from the firstelectrical stimulus by the calculated fraction of the tremor period,wherein the calculated fraction is at least about a quarter of thetremor period.
 21. The method of claim 20, wherein the calculatedfraction is one half of the tremor period, wherein the first electricalstimulus comprises a frequency of about 150 Hz, wherein analyzing datacomprises performing a frequency analysis of the spectral power ofmotion data on a predetermined length of time of the motion data,wherein the frequency analysis is restricted to between about 4 Hz toabout 12 Hz, and wherein the first electrical stimulus and the secondelectrical stimulus comprise burst stimuli.
 22. The method of claim 20,wherein the calculated fraction is one half of the tremor period. 23.The method of claim 20, wherein the calculated fraction is one quarterof the tremor period.
 24. The method of claim 20, wherein the firstelectrical stimulus comprises a frequency of between about 50 Hz toabout 300 Hz.
 25. The method of claim 20, wherein the first electricalstimulus comprises a frequency of about 150 Hz.
 26. The method of claim20, wherein the first electrical stimulus comprises a burst stimulus.27. The method of claim 20, wherein analyzing data comprises performinga frequency analysis of the spectral power of motion data on apredetermined length of time of the motion data, wherein the frequencyanalysis is restricted to between about 4 Hz to about 12 Hz.
 28. Amethod for transcutaneously stimulating afferent peripheral nerves of apatient, the method comprising: measuring one or more characteristics ofa resonant circuit of the patient using one or more wearable sensors;analyzing data from the one or more wearable sensors to calculate afraction of a period of the resonant circuit; positioning a firstperipheral nerve effector on the patient's skin to stimulate a firstafferent peripheral nerve; positioning a second peripheral nerveeffector on the patient's skin to stimulate a second afferent peripheralnerve; delivering a first electrical stimulus to the first afferentperipheral nerve through the first peripheral nerve effector; anddelivering a second electrical stimulus to the second afferentperipheral nerve through the second peripheral nerve effector, whereinthe second electrical stimulus is offset in time from the firstelectrical stimulus by the calculated fraction of the period of theresonant circuit, wherein the calculated fraction is selected from thegroup consisting of one half of the period of the resonant circuit, onequarter of the period of the resonant circuit, and three fourths of theperiod of the resonant circuit.
 29. The method of claim 28 furthercomprising repeating the first electrical stimulus and the secondelectrical stimulus in cycles, wherein the calculated fraction is onehalf of the tremor period, wherein analyzing data comprises performing afrequency analysis of the spectral power of data on a predeterminedlength of time of the data, wherein the first electrical stimulus andthe second electrical stimulus comprise burst stimuli, and wherein thepatient is a stroke patient.
 30. The method of claim 20, wherein thecalculated fraction is one half of the tremor period.
 31. The method ofclaim 20, wherein the calculated fraction is one quarter of the tremorperiod.
 32. The method of claim 20, further comprising varying thefrequency of the first electric stimulus over time.
 33. The method ofclaim 20, further comprising repeating the first electrical stimulus andthe second electrical stimulus in cycles.
 34. The method of claim 29,further comprising introducing random temporal delays between thecycles.
 35. The method of claim 29, wherein the patient is a strokepatient.
 36. A system for transcutaneously stimulating afferentperipheral nerves, the system comprising: one or more wearable sensorsmeasuring one or more characteristics of a resonant circuit of thepatient; a controller configured to analyze data from the one or morewearable sensors to calculate a fraction of a period of the resonantcircuit; a first peripheral nerve effector on the patient's skin tostimulate a first afferent peripheral nerve; a second peripheral nerveeffector on the patient's skin to stimulate a second afferent peripheralnerve, wherein the controller is configured to cause the system to:deliver a first stimulus to the first afferent peripheral nerve throughthe first peripheral nerve effector; and deliver a second stimulus tothe second afferent peripheral nerve through the second peripheral nerveeffector, wherein the second stimulus is offset in time from the firstelectrical stimulus by the calculated fraction of the period of theresonant circuit, wherein the calculated fraction is selected from thegroup consisting of one half of the period of the resonant circuit, onequarter of the period of the resonant circuit, and three fourths of theperiod of the resonant circuit.
 37. The system of claim 36, wherein thecontroller is further configured to cause the system to: repeat thefirst stimulus and the second stimulus in cycles, wherein the calculatedfraction is one half of the tremor period, wherein analyzing datacomprises performing a frequency analysis of the spectral power of dataon a predetermined length of time of the data, wherein the firstelectrical stimulus and the second electrical stimulus compriseelectrical burst stimuli, and wherein the patient is a stroke patient.38. The system of claim 36, wherein the calculated fraction is one halfof the tremor period.
 39. The system of claim 36, wherein the patient isa stroke patient.